Major Depressive Disorder (MDD) is a debilitating mood disorder associated with significant morbidity and mortality. Different classes of antidepressants act through unique mechanisms on specific, yet distinct neurotransmitter systems. It is a noteworthy coincidence that inhibition of glycogen synthase kinase-3 (GSK-3) is a common molecular consequence of treatment with diverse classes of antidepressants as well as mood stabilizers. We have forwarded the hypothesis that GSK-3 is the molecular target of lithium, a mood stabilizer, and modulates several antidepressant-sensitive behaviors. GSK-3 participates in multiple intracellular pathways including Wnt and insulin signaling. In the context of active Wnt signaling, GSK-3 is inhibited, resulting in the accumulation of the transcription factor -catenin. Thus lithium recapitulates Wnt/-catenin signaling by inhibiting GSK-3. During the course of our studies, we found several antidepressant-sensitive behaviors that were similarly affected by lithium. It is an intriguing parallel that lithium and antidepressants inhibi GSK-3 and affect mouse behaviors similarly. Indeed, heterozygous loss of GSK-3b mimicked the effect of antidepressants on these tests. The critical molecular effectors(s) downstream of GSK-3, relevant to the behavioral effects of antidepressant treatment have yet to be identified. This proposal will test the hypothesis that hypoxia-induced factor 1 (Hif-1a), recently discovered as a modulator of Wnt/-catenin signaling, is required for the effects of lithium and the antidepressants, imipramine and fluoxetine on behavior. Remarkably, lithium and antidepressants also enhance adult neurogenesis as a common cellular correlate! Enhanced hippocampal neurogenesis has been proposed as an integral component of the response to antidepressant and mood stabilizing therapy, yet little is known regarding the effect of antidepressants on neurogenesis. Wnt/-catenin signaling is critical for adult neurogenesis in the hippocampus. In a recent collaboration we found that Hif-1a regulates Wnt/-catenin transcription in embryonic stem cells and neural stem/progenitor cells but not in differentiated neurons. Neuron-specific deletion of Hif-1a in mice results in a severe adult neurogenesis defect in the hippocampus. Remarkably, the neurogenesis defect in Hif-1a KO mice can be rescued by inhibition of GSK-3 or stabilization of -catenin, both of which activate downstream Wnt signaling. These novel findings demonstrate a requirement for Hif-1a in neurogenesis and a novel mechanism of regulating Wnt/-catenin mediated transcription unique to NSCs. This proposal will test the hypothesis that Hif1a is required for antidepressant-induced enhancement of neurogenesis and that antidepressants act directly on NSCs. This proposal will determine the impact of Hif-1a deletion on Wnt/-catenin signaling and the ability antidepressants to rescue Hif-1a KO phenotypes at the molecular, cellular and behavior level. A new connection between hypoxia signaling and the actions of mood stabilizers and antidepressants could lead to a better understanding of and new approaches for the treatment of affective disorders. PUBLIC HEALTH RELEVANCE: Major Depressive Disorder (MDD) is a debilitating mood disorder associated with significant morbidity and mortality. Enhancement of neurogenesis is required for the effect of antidepressants on several pre-clinical behaviors. However, the mechanisms through which antidepressants act on neural stem/progenitor cells are not fully understood. We recently found that the stem cell niche in the adult hippocampus is relatively hypoxic and mice lacking the hypoxia-induced factor-1 (Hif-1a) gene have a profound defect in adult neurogenesis. This proposal explores the hypothesis that Hif-1a regulates adult neurogenesis and plays a central role in the neurogenic and behavioral responses to antidepressants. A new connection between hypoxia signaling and the actions antidepressants could lead to a better understanding of and new approaches to the treatment of affective disorders.